Treatment of withdrawal symptoms to aid in nicotine use cessation with Passiflora incarnata

ABSTRACT

The present invention relates to the treatment of withdrawal and craving symptoms as an aid in smoking cessation by administration of one or more dosages of a medication containing  Passiflora incarnata.

This application claims priority of U.S. provisional application No.61/548,245 filed on Oct. 18, 2011 and included herein in its entirety byreference.

COPYRIGHT NOTICE

A portion of the disclosure of this patent contains material that issubject to copyright protection. The copyright owner has no objection tothe reproduction by anyone of the patent document or the patentdisclosure as it appears in the Patent and Trademark Office patent filesor records, but otherwise reserves all copyright rights whatsoever.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a method of treating an individualduring nicotine withdrawal. In particular, the present invention relatesto treating an individual who is addicted to nicotine with Passifloraincarnata, or an extract thereof, to prevent withdrawal and cravingsymptoms during nicotine cessation to aid in smoking cessation.

2. Description of Related Art

Tobacco is the single greatest cause of disease and premature deathtoday in America and is responsible for more than 440,000 deaths eachyear. Despite the morbidity, mortality, and cost to smoking, nearly 21%of all adult Americans continue to smoke.

Nicotine, the active ingredient responsible for the addictive nature ofcigarette smoking and use of other nicotine containing products such assnuff, chew tobacco, and the like, exerts excitatory and inhibitorypharmacologic effects which account for its stimulating yet calmingeffects. The compound binds to central nicotinic receptors causingrelease of the neurotransmitter dopamine in the mesolimbic area, thecorpus striatum, and the frontal cortex. An increase in dopamine levelsin the nucleus accumbens has been shown related to the addictiveproperties of nicotine.

Dopaminergic projection to the nucleus accumbens arises from neurons inthe central tegmental area (VTA). Dopamine release from VTA projectionsis related to both excitatory and inhibitory inputs. In rat studies, ithas been demonstrated that the inhibitory input to the VTA neurons areprimarily GABAergic. Therefore, GABA agonists which have an action toinhibit neuronal outflow via this pathway may theoretically modulatedopamine release.

Nicotine replacement therapy (NRT), bupropion and varenicline arecurrently FDA approved as smoking cessation aids in the United States.

Extracts of passion flower have been used in traditional and herbalmedicines for anxiety, insomnia, and seizures, but controlled clinicalstudies of passion flower extract for these indications are limited.Passion flower extract has been examined in double blind studies andshown to treat generalized anxiety disorder similar to oxazepram, tohelp patients through opiate withdrawal, and to help alleviatepresurgical anxiety. In laboratory rodents, passion flower extract orsingle chemical constituents of passion flower have been shown to besedative, anxiolytic and anticonvulsant. Moreover, numerous studies inlaboratory rodents have demonstrated that whole extracts or a specificbenzoflavone moiety from passion flower are anxiolytic, antitussive andaphrodisiac and may reduce certain kinds of drug dependence other thannicotine. They have shown that the benzoflavone drug, given togetherwith the addictive agent during the induction of dependence, reduced thesymptoms of antagonist-precipitated withdrawal to morphine, alcohol,nicotine, diazepam and Δ9-tetrahydrocannabinol.

As demonstrated in previous studies, an acute injection of nicotine torats results in increased locomotion, and daily injections result insensitization to this effect. This hyperlocomotion effect is used as amodel of nicotine addiction or withdrawal and agents that block theexpression of this hyperlocomotion are considered useful in treating thesigns of withdrawal from nicotine in humans.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to the discovery that an administration ofPassiflora incarnata as whole plant or an extract, such as an alcoholextract in a therapeutically effective amount would reduce the severityof the symptoms of nicotine withdrawal during smoking cessation.

Accordingly, one embodiment of the invention comprises a method forreducing nicotine withdrawal symptoms associated with nicotine productcessation in a patient in need thereof comprising administering to thepatient a composition comprising Passiflora incarnate, or an extractthereof, in a pharmaceutically acceptable carrier in a therapeuticallyeffective amount.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-3 show the results of treatment of nicotine habituation withPassion flower treatment.

DETAILED DESCRIPTION OF THE INVENTION

While this invention is susceptible to embodiment in many differentforms, there is shown in the drawings and will herein be described indetail specific embodiments, with the understanding that the presentdisclosure of such embodiments is to be considered as an example of theprinciples and not intended to limit the invention to the specificembodiments shown and described. In the description below, likereference numerals are used to describe the same, similar orcorresponding parts in the several views of the drawings. This detaileddescription defines the meaning of the terms used herein andspecifically describes embodiments in order for those skilled in the artto practice the invention.

The terms “a” or “an”, as used herein, are defined as one or as morethan one. The term “plurality”, as used herein, is defined as two or asmore than two. The term “another”, as used herein, is defined as atleast a second or more. The terms “including” and/or “having”, as usedherein, are defined as comprising (i.e., open language). The term“coupled”, as used herein, is defined as connected, although notnecessarily directly, and not necessarily mechanically.

The terms “about” and “essentially” mean±10 percent.

The term “comprising” is not intended to limit inventions to onlyclaiming the present invention with such comprising language. Anyinvention using the term comprising could be separated into one or moreclaims using “consisting” or “consisting of” claim language and is sointended.

Reference throughout this document to “one embodiment”, “certainembodiments”, and “an embodiment” or similar terms means that aparticular feature, structure, or characteristic described in connectionwith the embodiment is included in at least one embodiment of thepresent invention. Thus, the appearances of such phrases or in variousplaces throughout this specification are not necessarily all referringto the same embodiment. Furthermore, the particular features,structures, or characteristics may be combined in any suitable manner inone or more embodiments without limitation.

The term “or” as used herein is to be interpreted as an inclusive ormeaning any one or any combination. Therefore, “A, B or C” means any ofthe following: “A; B; C; A and B; A and C; B and C; A, B and C”. Anexception to this definition will occur only when a combination ofelements, functions, steps or acts are in some way inherently mutuallyexclusive.

The drawings featured in the figures are for the purpose of illustratingcertain convenient embodiments of the present invention, and are not tobe considered as limitation thereto. Term “means” preceding a presentparticiple of an operation indicates a desired function for which thereis one or more embodiments, i.e., one or more methods, devices, orapparatuses for achieving the desired function and that one skilled inthe art could select from these or their equivalent in view of thedisclosure herein and use of the term “means” is not intended to belimiting.

All patents, patent applications and literature cited in thisdescription are incorporated herein by reference in their entirety. Inthe case of inconsistencies, the present disclosure includingdefinitions will prevail.

As used herein the phrase “Passiflora incarnata” refers to the plant inany of its forms including the whole flower, the dried flower, andaqueous solutions, extracts and tinctures including extracts of alcoholand the like. Ethanol extracts for example in 25% ethanol are within thescope of the extracts of the present invention. Exact dosaging willdepend on the particular strain of plant, the route of administration,the formulation used to administer the composition, and the like. Oneskilled in the art with the knowledge of the present invention thatPassiflora incarnata can be used to treat nicotine withdrawal and aid innicotine product cessation, can easily and without undue experimentationdetermine the right amount of composition to administer to an individualin light of the disclosure herein including the definition of atherapeutic amount.

In addition, pharmaceutically acceptable carriers may be used in thecompositions of the present invention. The term “pharmaceuticallyacceptable carrier” refers to a carrier that may be administered to apatient, together with Passiflora incarnata, and which does not destroythe pharmacological activity thereof and is nontoxic when administeredin doses sufficient to deliver a therapeutic amount of the compositionsof the present invention.

Non-limiting exemplary examples of pharmaceutically acceptable carriersinclude, ion exchangers, alumina, aluminum stearate, lecithin,self-emulsifying drug delivery systems (SEDDS) such as dalpha-tocopherol polyethyl-eneglycol 1000 succinate, or other similarpolymeric delivery matrices or systems, serum proteins such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as alpha-, beta-, and gamma-cyclodextrin,or chemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-.beta.-cyclodextrins, or othersolublized derivatives may also be advantageously used to enhancedelivery of therapeutically-effective Passiflora incarnate.

The compositions of the present invention may also contain adjuvantssuch as preservative, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and antifungal agents, for example,paraben, chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like.

As used herein the phrase “nicotine product cessation” refers tocessation of the use of products that contain nicotine. Smokingcessation, such as use of cigarettes, cigars, pipes, and the like, aswell as chew tobacco, snuff, and the like are all within thisdefinition. The intention is the cessation of products that anindividual is addicted to or otherwise is trying to quit which containsnicotine supporting a nicotine habit. As used herein where the phrase“smoking cessation” is used it also encompasses cessation of anynicotine containing product.

As used herein, “therapeutically effective amount” or “therapeuticallyeffective dose” means a nontoxic but sufficient amount of an activeagent to provide the desired therapeutic effect (i.e., minimizingnicotine withdrawal symptoms). It will be understood, however, that thetotal usage (daily or otherwise) of the compounds and compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific therapeuticallyeffective dose level for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; activity of the specific compound employed; thespecific composition employed, the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of the compound at levels lower than those required toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved. The dosage ranges for thepresent invention are all well above the current minimums used in theart. Starting dosages where the dosage is tapered upward would alsostart at a much higher than the minimal amounts than occur in presentpreparations. A minimum dosage would be in the range of 2 gm per day andmay range up to 60 gm or more as needed for the individual. Thepharmaceutical compositions of the present invention may be administeredorally, intracisternally, intravaginally, intraperitoneally, topically(as by powders, ointments, drops or transdermal patch), rectally, orbucally. In one embodiment, the pharmaceutical compositions of thepresent invention comprising a Passiflora incarnata medication areadministered orally.

The pharmaceutical compositions of the present invention may be in aform suitable for transdermal administration. By “transdermal drugdelivery” is meant administration of a drug to the skin surface of anindividual so that the drug passes through the skin tissue and into theindividual's blood stream, thereby producing a systemic effect. The term“transdermal” is intended to include “transmucosal” drug administration,i.e., administration of a drug to the mucosal (e.g., sublingual, buccal,vaginal, rectal) surface of an individual so that the drug passesthrough the mucosal tissue and into the individual's blood stream.

The pharmaceutical compositions of the present invention may be in aform suitable for oral use, for example, as tablets, lozenges, aqueousor oily suspensions, dispersible powders or granules, emulsions, hard orsoft capsules, syrups or elixirs. Compositions intended for oral use maybe prepared according to any method known to the art for themanufacturer of pharmaceutical compositions and such compositions maycontain one or more agents such as, for example, sweetening agents,flavoring agents, coloring agents and the like, in order to provide apharmaceutically elegant and palatable preparation.

Tablets contain the active ingredients in admixture with nontoxicpharmaceutically acceptable excipients which are suitable formanufacture of tablets. These excipients may be inert diluents, forexample, calcium carbonate, sodium carbonate, lactose, calcium phosphateor sodium phosphate; granulating and disintegrating agents, for example,alginic acid, maize starch or; binding agents, for example, acacia,gelatin or starch, and lubricating agents, for example, magnesiumstearate or stearic acid. The tablets may be uncoated or they may becoated by known techniques to delay disintegration and absorption in thegastro-intestinal tract and thereby provide an even longer sustainedaction over a period of time. The tablets may be chewable ornon-chewable and designed to desired weight, potency and hardnessthrough well known skills in the pharmaceutical arts.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredients are mixed with an inert solid diluent,for example, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with a suitableoil medium, for example, arachis oil, liquid paraffin or olive oil.

Formulations for oral use may also be presented as lozenges wherein theactive ingredients are mixed into a hard candy composition. Suitablehard candy compositions can be made from varying, but highlyconcentrated, sucrose solutions including corn syrup as a secondessential ingredient. Other known hard candy compositions may utilizeany suitable good tasting, sweet excipient other than sucrose.

Aqueous suspensions contain the active ingredients in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients or combinations thereof may be suitable suspending agents,for example, alginates, carboxymethylcellulose, carboxypolymethylene,carrageenan, colloidal silicon dioxide, corn starch, flowable starch,gelatin, guar gum, gum acacia, gum tragacanth, hydroxypropylcellulose,hydroxypropylmethylcellulose, maltodextrin, methylcellulose,microcrystalline cellulose, pectin, polyethylene glycol 800, polyvinylalcohol, polyvinylpyrrolidone, sodium alginate, sodium carboxymethylcellulose or xanthane gum; dispersing or wetting agents may be anysuitable naturally occurring phosphatides, for example, lecithin, orcondensation products of an alkaline oxide with fatty acids, forexample, polyoxyethylene stearate, or condensation products of ethyleneoxide with long chain aliphatic alcohols, for example,heptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol, for example,polyoxyethylene sorbitol monoleate, or condensation product of ethyleneoxide with partial esters derived from fatty acids and hexitol andanhydrides, for example, polyoxyethelyne sobirtan monooleate, or water.The aqueous suspensions may also contain one or more suitablepreservatives, for example, ethyl, or n-propyl, p-hydroxy benzoate, oneor more suitable coloring agents, one or more suitable flavoring agentssuch as, cinnamon, chocolate, fruit flavors cherry, grape, orange,strawberry, etc.), menthol, mints, vanilla and combination of two ormore thereof, one or more suitable sweetening agents, such as calciumcyclamate, dextrose, fructose, galactose, glucose, glycerin, maltose,mannitol, mannose, ribose, partially hydrolyzed starch solids, partiallyhydrolyzed corn syrup solids, sodium cyclamate, sorbital, inulin,sucralose, sucrose, xylitol, or xylose, and one or more suitablecoloring agents.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent, and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents may be exemplified by those already mentioned above.Additional suitable excipients, for example, sweetening, flavoring, andcoloring agents, may also be present.

Syrups and elixirs may be formulated with suitable sweetening agents,for example, one or more of glycerol, sorbitol, inulin, sucrose, orxylose. Such formulations may also contain suitable demulcents,preservatives such as citric acid, flavoring and coloring agents.

The individual compound of the pharmaceutical compositions may beadministered alone or with other compositions, either substantiallytogether or simultaneously, in separate or combined pharmaceuticalformulations. By “substantially together”, the active ingredients of thecomposition of the invention are administered to a patient in separatedosage forms, such that the active ingredients are administered eithersimultaneously or within a period of time, such that the patientreceives benefit of the aggregate effects of the separate dosage forms.For example, the active ingredients may be taken together or within afew seconds to at least about 30 minutes of one another. Accordingly,methods of treatment of the present invention, therefore, includeadministration of the individual compounds of such combinations eithersubstantially together or simultaneously in separate or combinedpharmaceutical formulations. When administering or taking the activeingredients substantially together, but separately in the same ordifferent dosage forms, the order in which they are administered oringested is not critical.

Thus, according to a further aspect, the invention provides a method oftreating nicotine withdrawal symptoms associated with smoking cessation,comprising administering to a patient in need thereof, a therapeuticallyeffective amount of a medication comprising Passiflora incarnata. In oneembodiment, a patient is treated by injecting the patient with thePassiflora incarnata medication of the present invention. In yet anotherembodiment the medication is administered orally.

In one embodiment, the medication is administered orally. The medicationcan be self administered and is given as a single dose or multiple dosesover a period of weeks. The administration can continue until thenicotine product use has completely stopped and the appearance ofsymptoms has been alleviated. This will be different from person toperson and will depend at least on the level of nicotine addiction, andto some extent, the personality of the individual taking the product.Typically, an effective therapeutic dose ranges from about 1.8 cc toabout 3.0 cc. In other embodiments it is from 5 to 15 cc and in otherembodiments it is over 15 cc as necessary to administer atherapeutically effective amount.

In another embodiment of the present invention, in place of aninjection, the medication is administered transdermally via, forexample, a scopolamine type patch, and/or orally, for example, viacapsules or tablets according to accepted pharmacological principals

While an administration is designed to obtain immediate and high levelsof activity, a maintenance regime is designed to maintain lower levelsof activity during the remainder of the withdrawal period. In anotherembodiment, the method of the present invention further comprises a stepof continuing the effects of the medication administered via continuedadministration. Oral and transdermal agents, in addition to Passifloraincarnate, may be subsequently ingested by the patient to providecontinued relief from craving and withdrawal symptoms of nicotine untilthe physiological effects of nicotine withdrawal are sufficientlyminimized. Such non-limiting exemplary oral agents include nicotinepatches. In an embodiment, the patient can begin taking the prescribedadditional agent the day following receipt of the injected or otherwiseadminister Passiflora incarnata medication and continue for about twoweeks, or until nicotine withdrawal symptoms are sufficiently minimized.While this method addresses the physiological aspects of nicotinewithdrawal, there are, however, also psychological associations linkedto smoking cigarettes which must be overcome for successful smokingcessation.

The invention provides in a further embodiment, a step for alleviatinganxiety associated with nicotine withdrawal. Anxiolytic agents areprescribed using accepted pharmacological principals and subsequentlyingested as prescribed by a patient. As used herein “anxiolytic agent”means any compound or composition having anxiolytic properties.Non-limiting examples of an anxiolytic include abecarnil, alpidem,benzodiazepines, buspirone, chlormezanone, chlorpromazine, clonidine,flupirilene, hydroxyzine, trandospirone, and meprobamate. In oneembodiment, the patient begins taking the anxiolytic agent followingreceipt of the Passiflora incarnata medication. Alternatively, theanxiolytic agent can be administered simultaneously or substantiallytogether with the Passiflora incarnata medication, for example, combinedinto and administered as a component of the Passiflora incarnatamedication administered by the desired route.

The invention also provides in a further embodiment, a step foralleviating depression which can also be associated with nicotinewithdrawal. Antidepressants are prescribed using acceptedpharmacological principals and subsequently ingested as prescribed by apatient. In one embodiment, antidepressants such as serotonin reuptakeinhibitors, bupropion, and buspirone are prescribed prior to or inconjunction with a patient's receipt of the Passiflora incarnatamedication.

In a further embodiment, the invention also provides several methods ofdisassociating the habits of smoking by implementing a behavioralmodification program and/or hypnosis or the like in combination with thePassiflora incarnata administration. These associations may be addressedprior to administration of the Passiflora incarnata medication in orderto enhance the success of a smoking cessation program. Unfortunately,many patients resume smoking well after the physiological addiction hasresolved. Usually this is due to poor coping habits and lack of support.Therefore, smoking cessation success rates may also be enhanced byroutine support and counseling after the physiologic withdrawal hasresolved. Non-limiting examples of the formats in which smokingcessation support and counseling is offered include, telephoneconference calls, internet discussion boards, internet chat rooms, groupmeetings and individualized counseling sessions. Counseling and supportmay also be provided to a patient through various media, such as videotapes, CDs, DVDs and audiotapes having recorded thereon variouseducational and support materials for the cessation of smoking.

In order to further illustrate the present invention and the advantagesthereof, the following specific non-limiting examples are given, itbeing understood that these examples are intended only to beillustrations of the effectiveness of the present invention withoutserving as a limitation on the scope of the present invention in thetreatment of smoking cessation withdrawal symptoms.

EXAMPLES

Drug Treatment of Rats

Male Wistar rats (Charles River, Raleigh, N.C.) were provided with foodand water ad libitum on a 12 hour light/dark cycle for 2-3 weeks beforebeginning any treatments. For all experiments, rats were approximately45-65 days old and weighed between 148 and 195 g at the beginning of anexperiment. Injections of nicotine or its vehicle (water) weresubcutaneous (s.c.) administered at 0.4 mg/kg nicotine (Sigma Aldrich,St. Louis, Mo.) and 2 ml/kg. Injections of aqueous passion flowerextract (Nature's Answer, Hauppage, N.Y.) or vehicle (1:1glycerin:water) were intraperitoneal (i.p.) administered at 800 mg/kgand 0.16 ml/kg.

Assessment of Time to Habituation and of Acute Nicotine on SpontaneousActivity

Drug-naive rats were placed individually in an open field fordetermination of spontaneous activity using the Limelight video trackingsystem (ActiMetrics, Wilmette, Ill.). Each rat was monitored in the openfield for 30 minutes to determine the time course of habituation.Immediately afterward, each rat was injected with vehicle that wassubsequently used for nicotine injection at 2 ml/kg and the rats weremonitored for 50 minutes. Then each rat was removed from the chamberbriefly to be injected s.c. with 0.4 mg/kg nicotine and monitored foranother 90 minutes.

Assessment of the Effect of Passion Flower Extract on NicotineSensitization

To produce nicotine sensitization, rats were injected once/day for 4consecutive days with either nicotine or vehicle. On day 5, known as thetest day, rats were divided into four groups; half of those that hadreceived vehicle on days 1-4 were pre-treated with passion flowerextract (vehicle-passion flower group) and the other half with vehicle(vehicle-vehicle group). Analogously, half of the rats that receivednicotine on days 1-4 received a pre-treatment of i.p. 1:1 water:glycerin(nicotine-vehicle group) on day 5, while the other half was given apre-treatment of i.p. passion flower extract (nicotine-passionflowergroup). Each rat was monitored in the open field for 100 consecutiveminutes, starting approximately 23 hours after the day 4 nicotinetreatment. Before any injections on day 5, rats were placed in theactivity chambers until an injection of passion flower extract orvehicle at 25 minutes, then monitored for another 25 minutes, at whichpoint all rats received an injection of nicotine and were monitored for50 additional minutes.

Data Analysis

Mean velocity (in cm/s) over each 1 sec period was extracted using theLimeLight software and that data was used to calculate the average andSEM of the mean velocities for each 5 minute interval for each treatmentgroup. Figures show the time at the end of the 5 minute period (e.g., 10minutes is the 5-10 minute interval). In the preliminary assay ofnicotine versus vehicle, there were 6 rats and in the chronic nicotinestudy there were 8-10 rats in each group.

Results

In the first assays, the length of time that it took the rats tohabituate to the spontaneous activity chambers and the time course ofthe effects of a single dose of nicotine on spontaneous activity wasdetermined. Drug-naïve rats were placed in the open field chambers andtheir activity recorded until their spontaneous activity had largelysubsided. The amount of spontaneous activity in the first 5 minutes washigh, 3.5 cm/s average velocity, and decreased to low levels, 0.5 cm/s,during the 25-30 minute interval (FIG. 1). Next, each rat was given as.c. injection of vehicle and immediately returned to the open fieldchamber for another 50 minutes. It was noted that the spontaneousactivity was initially higher than at the end of the habituation period,1.5-1.7 cm/s, but not as high as when first introduced to the chamber.Again, it took about 25 minutes for the level of spontaneous activity todecrease to between 0.5 and 0.7 cm/s where it remained for the rest ofthe session. At the end of this 50 minute period, rats were injecteds.c. with 0.4 mg/kg nicotine and again returned to the chambers foranother 90 minutes (FIG. 1). While the amount of spontaneous activityinitially rose from the first to the second 5-minute interval, from thatpoint it generally declined from 2.5 cm/s to 0.8 cm/s over the first 60minutes. During the last 30 minutes, the level of spontaneous activityremained low at between 0.6 and 0.1 cm/s. The amount of spontaneousactivity was initially similar to, and not significantly different from,that seen in the vehicle-treatment phase. Activity after nicotinetreatment peaked from 5-15 minutes after injection (intervals of 5-10and 10-15 minutes), and was significantly different from vehicletreatment in the intervals between 10 and 35 minutes after injections(with the exception of the interval from 15-20 minutes) by 2-way ANOVA(treatment p<0.0001) followed by Bonferroni's posttest at p<0.05. Afternicotine treatment, rats moved between 2.5 and 1.4 cm/s (an average of1.9±0.2 cm/s) during the 10-35 minute intervals, while during the sameperiod after vehicle treatment the values were between 1.3 and 0.3 cm/s(an average of 0.8±0.1 cm/s).

Once the habituation period and time to the peak effect of a dose ofnicotine was determined, the nicotine sensitization experiments began.In these experiments, rats were sensitized to nicotine by theadministration of 0.4 mg/kg s.c. nicotine or vehicle (as a control) ondays 1-4, and the testing was done on day 5. Similar to the preliminarystudy above, the rats began at a high level of spontaneous activity ofapproximately 3.5 cm/s then habituated to the open field chambers (FIG.2). At the last measurement during the habituation phase taken at 15-20minutes, the activity for the four groups averaged 1.4±0.1 cm/s (FIG.1). Passion flower extract or its vehicle was administered i.p. between20 and 25 minutes and activity was assessed while allowing time for theextract to be absorbed. The activity of all groups remained low duringthis period with an average of 0.32±0.03 cm/s from 25-45 minutes (FIG.2). Between 45 and 50 minutes, nicotine was injected s.c. into all rats.Activity increased and peaked in all four groups at 60-65 minutes (FIG.2). By 65-70 minutes the nicotine-vehicle group exhibited significantlygreater activity than the other three, and this difference persisted upto the 90 minute time point (except that the difference at 75-80 minuteswas not statistically significant). Significance was determined by 2-wayANOVA where the effect of treatment was p<0.0001. To determinedifferences between groups at specific tune points, one-way ANOVAscomparing all four groups were performed at each time interval. In eachcase where a difference was noted above, the nicotine-vehicle group hadsignificantly greater activity from the other three, while none of theother groups were different from each other.

This experiment determined that the passion flower extract couldantagonize the expression of motor sensitization by nicotine. Followingthe daily nicotine treatments that produced sensitization, the challengedose of nicotine on the test day caused an increase in locomotion abovewhat was seen after an acute or first dose of nicotine. There are twoways in which pharmacotherapies for nicotine addiction are tested inmotor sensitization models. One is known as antagonism of motorsensitization, and involves giving the test compound concurrent withnicotine during the induction of dependence, but not on the day of thechallenge dose of nicotine. The other is known as antagonism of theexpression of motor sensitization, and involves giving the test compoundonly once shortly before the administration of the challenge dose ofnicotine. If a test drug treatment blocks the increased response to thechallenge dose of nicotine in this model, it indicates decreases in thesigns of nicotine withdrawal. In these studies, the nicotine-vehicle andnicotine-passion flower groups were the nicotine-sensitized groups inwhich motor sensitization should have been induced. The nicotine-vehiclegroup (control nicotine sensitized group) showed significantly greateractivity than the vehicle-vehicle group following the challenge dose ofnicotine, reflecting nicotine sensitization. Comparison of thenicotine-vehicle and nicotine-passionflower groups illustrates thatpassion flower extract antagonized the expression of motorsensitization, since the nicotine-passion flower group showed the samelevel of activity as the non-sensitized vehicle-vehicle control groupfollowing nicotine challenge.

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What is claimed is:
 1. A method for reducing nicotine cravingsassociated with nicotine product use in a patient in need thereofconsisting of administering to the patient a plant composition, theplant composition consisting of a water extract of Passiflora incarnata.2. The method according to claim 1 wherein the plant compositionconsists of administering to the patient between 2 grams per day and 60grams per day of the water extract of Passiflora incarnata.
 3. Themethod according to claim 1 wherein the nicotine product is selectedfrom the group comprising snuff, chew tobacco and smoking tobacco. 4.The method according to claim 1 wherein the route of administration isoral.
 5. The method according to claim 1 wherein the route ofadministration is subcutaneous.
 6. The method according to claim 1wherein a single dose is administered.